Cocaine was considered to be a “safe” party drug in the high-flying ’80s when a young psychiatrist decided to see what it did to the brain.

Using an imaging technique called PET, Nora Volkow, M.D., and her colleagues at the University of Texas in Houston documented areas of “deranged” cerebral blood flow resembling tiny strokes in people who took copious amounts of the drug.

Cocaine was known to constrict blood vessels. Heavy use of the drug had been linked to fatal heart attacks and strokes. Yet their findings at first were greeted with skepticism.

Then in 1986, University of Maryland basketball star Len Bias collapsed and died of a cocaine overdose, and the tide began to turn. “When you go against the current, it takes time to change its course,” says Volkow, now director of the National Institute on Drug Abuse (NIDA).

Just as she once helped dislodge widely held notions about cocaine, today this strong-minded scientist is determined to transform the way addicts are treated—or, more often, not treated—by the medical profession and the criminal justice system.

While she sees this a part of her duty as a physician, to serve the most vulnerable members of society, Volkow also acknowledges the world-changing legacy of her great-grandfather, exiled Russian revolutionary Leon Trotsky.

“It’s not religious; it’s just a sense of humanity, a sense of being part of humankind,” she says, her words wrapped in the melodic tones of her native Mexico. “You are alive, you have a certain talent, and you have a responsibility to use it to help others.”

“This is the smartest person I know,” says Joanna Fowler, Ph.D., senior chemist at Brookhaven National Laboratory in Upton, N.Y., who has worked with Volkow since the mid-1980s. “People just glom onto her. She’s like pouring out ideas all day… She can take a problem and very easily see through it; see relationships, simplify things.”

At the same time, says Fowler, “she’s a very compassionate person ... very much involved in the social impacts of drug abuse.

“Drug addiction impacts enormously even on things that you wouldn’t normally think of, like cancer in cigarette smoking, like heart disease, like violence with alcoholics, and accidents and AIDS,” she says. “I think we’re very fortunate to have a person like Nora.”

“I see her as a warrior fighting against a universal enemy,” adds her younger sister, Natalia Volkow, Ph.D. “It’s such a horrible enemy and so difficult to beat. And that’s why I think she chose this subject of study. Nora has never taken the easy way in life, never.”

Volkow, born in 1956, displays an intriguing amalgam of traits: athletic drive and stamina (the former competitive swimmer runs six miles every morning before work); an exuberant sense of wonder about the world; and a knack of looking at science through the eyes of an artist (a painter, her older sister is Mexican poet Verónica Volkow).

Most importantly, she says, “I’m a scientist. I’ve always loved science. That’s how I see myself.”

So far in her career, Volkow has authored or contributed to more than 300 scientific articles. Through groundbreaking imaging studies of the brain’s frontal cortex and its dopamine-driven circuitry, she has helped reveal the neurobiological underpinnings of addiction, and how drug-induced changes in brain chemistry contribute to its hallmark craving, compulsion and loss of control.

Two paths

Addiction is not the only area that has come under Volkow’s sharp-eyed scrutiny.

Nora with her mother in 1980

Photos courtesy of Nora and Natalia Volkow

She and her Brookhaven colleagues also have linked long-term use of anti-psychotic drugs to the withdrawal and blunting of emotions seen in individuals with schizophrenia; showed how therapeutic doses of Ritalin and other stimulants can improve attention; and found evidence that dopamine, a chemical messenger important in drug addiction, may also play a role in over-eating and obesity.

“She really is one of those people who think very much into the future,” says former NIDA director Alan I. Leshner, Ph.D., CEO of the American Association for the Advancement of Science. “She’s always, in her own research, been leading the cutting edge… She has brought that to NIDA as well. That’s exactly where it ought to be.”

While she firmly believes in the disease model, Volkow is quick to point out that addiction is not simply the result of particular genes and brain chemicals. “Predisposition is not predetermination,” she told a congressional subcommittee last April. “Environment and other biological factors, including family, culture and community, are of great importance to the development of addiction and are essential to its prevention.”

Drugs aren’t the only way to treat addiction. Imaging studies can validate the effectiveness of cognitive and behavioral therapies, as well. Potentially they may help identify social interventions that protect young people from abusing drugs in the first place.

“I always take two paths,” Volkow explains, “one path that is going to lead us to the science and the knowledge that will really revolutionize the way that we treat drug addiction, so that five or 10 years from now we will be treating drug addiction completely differently.

Volkow administers a contrast agent prior to a PET study in 1990. In the background are research nurse Noel Netusil, R.N., (left) and technician Renee Modell, now a nuclear medicine physician.

Courtesy of Brookhaven National Laboratory

“But at the same time, developing strategies that can benefit those that are afflicted by addiction, or interventions that can prevent the use of drugs. We need to get science that looks into the future… but we also need to address the needs right now.”

Volkow’s path started in the house where her great-grandfather was murdered.

Born Lev Davidovich Bronstein, Trotsky was a brilliant political theorist and proponent of permanent worldwide revolution by the working class. Founder of the Red Army, he was second only to Vladimir Lenin during the early years of Bolshevik rule. After Lenin’s death in 1924, Trotsky was expelled from the Soviet Union when Joseph Stalin took control of the government and launched a purge of his rivals.

Trotsky lived for a few years in Turkey, then in France and Norway before eventually finding refuge in Mexico City, where he continued to write books critical of the Stalin regime. Family members who remained in the Soviet Union were imprisoned or shot. In 1940—shortly after his grandson Esteban moved from Turkey to join him—Trotsky was assassinated by one of Stalin’s agents.

Nora with her father. Esteban Volkov says he and his wife, who died in 1997, tried to nurture in their daughters an appreciation of the artistic and intellectual life—and freedom of expression. "I established an absolute true democracy in the family," he says. "There was no imposition. Each one could choose the career that she would like." Natalia earned a doctorate in information systems from the London School of Economics, and is a deputy director general of Mexico's National Institute of Statistics, Geography and Informatics. Her identical twin, Patricia, is a doctor and expert on AIDS.

Photos courtesy of Nora and Natalia Volkow

Esteban Volkov Bronstein became a chemist and married Palmira Fernández, a fashion designer from Madrid who had fled the Spanish Civil War. They had four daughters, and continued to live in Trotsky’s carefully preserved house (it is now a museum).

Volkov’s daughters, who end their last name with a “W” instead of the Russian “V,” gradually heard details of their great-grandfather’s story—but not from their father. “It was a very, very painful period, so he couldn’t really speak about it,” Nora explains.

They learned from the constant stream of visitors who knocked on Trotsky’s door.

“As little girls, whenever somebody rang the bell and asked us to guide them through the house, we did so, and that was a privilege,” recalls Natalia. “We usually took a long time talking to them—listening to them.”

On one occasion, a group of visitors from South America took the tour, and afterwards Nora got into a lengthy conversation about One Hundred Years of Solitude, which she was reading. Later she learned that one of the men with whom she had been talking all afternoon was the book’s author, Gabriel García Márquez.

The living brain

“She was a great reader of all kinds of books,” her father recalls. At the same time, “Nora always was a very warm and sweet person. She always showed a great love and passion for animals.”

Volkov is not in the least surprised at the meteoric rise of his middle daughter’s career. “Nora has a very basic principle,” he says. “She always had a very, very great respect for the truth.”

Fluent in four languages (including French and German), Volkow received her undergraduate and medical school training at the National Autonomous University of Mexico in Mexico City, where she was recognized as the best student of her undergraduate and medical school classes.

In 1981, after receiving her medical degree, she read an article in Scientific American about a new imaging technology called positron emission tomography (PET). She was mesmerized by the splotchy, brilliantly colored images of the living brain. In an instant, the direction of her life changed.

Instead of the applying for postgraduate study at the Massachusetts Institute of Technology, Volkow opted for residency training in psychiatry at New York University and the chance to work—in a collaborative research program—with the PET pioneers at Brookhaven, a Department of Energy-operated laboratory near the far end of Long Island.

Five years earlier, a Brookhaven team led by Fowler and Alfred P. Wolf, Ph.D., had produced a radiotracer for glucose, the brain’s primary fuel. Colleagues at the University of Pennsylvania used it to create the first images of the living human brain. The intensity of the color on the PET scan reflected the concentration of 18F-fluorodeoxyglucose (FDG), and thus where the brain was active.

By the early 1980s, the Brookhaven team—bolstered by an energetic psychiatry resident—was using PET to study the brains of people with schizophrenia. Their images revealed decreased brain activity in the frontal cortex of patients who had been taking anti-psychotic drugs like Thorazine for long periods of time. “The greater the decrease in brain activity, the greater the ‘poverty of thinking,’” Volkow says.

Anti-psychotic drugs like Thorazine were known to block the receptors for dopamine, a neurotransmitter that conveys signals between the frontal cortex and other parts of the brain. The frontal cortex, in turn, is involved in a host of cognitive and “executive” functions, from language and memory to impulse control and the ability to solve problems.

While the researchers were unable to determine how much of the withdrawal and blunting of emotions observed in the patients was due to the drugs, and how much to their disease, the study was one of the first to open up the frontal cortex through the window of PET.

After completing her residency in 1984, Volkow moved to the University of Texas in Houston to continue her research at a PET research center founded by cardiologist K. Lance Gould, M.D. Here her path turned again.

The university hospital had no patients with schizophrenia to study, Volkow recalls, but there were plenty of cocaine addicts. So, with the help of addiction specialist Kenneth Krajewski, M.D., and physicists Nizar Mullani and Stephen Adler, Volkow conducted the first PET studies of the brains of cocaine addicts.

At first, she says, no one believed the images of deranged blood flow, suggestive of stroke. It would be 1988—three years later—before their findings were published by the British Journal of Psychiatry.

By then, Volkow and Adler had married and had accepted positions at Brookhaven.

Volkow, who also joined the faculty in psychiatry at the State University of New York at Stony Brook, says she was tempted back by Wolf’s offer to label cocaine for her. “That was extraordinary,” she says, “because it actually opened up the first study to be able to look at the dynamics of these drugs in the brain.”

Making connections

Nora with her sister Natalia on the peak of Popocatépetl (the highest active volcano in the Northern Hemisphere), southeast of Mexico City

Photos courtesy of Nora and Natalia Volkow

Soon Volkow and her colleagues, who frequently included Wolf and Fowler, were labeling all sorts of things: D2, a receptor through which dopamine sends its signals; monoamine oxidase, an enzyme that breaks down dopamine; and methylphenidate (Ritalin), which was labeled by Yu-Shin Ding, Ph.D.

In 1993, the Brookhaven group reported that cocaine abusers had lower levels of the dopamine D2 receptor compared to normal controls. Reductions in receptor levels were associated with decreased metabolism, as measured by glucose consumption, particularly in the orbitofrontal cortex and cingulate gyrus.

The cingulate gyrus, a ridge of tissue deep in the brain, is part of the limbic system, associated with mood and emotions. What was surprising was the connection to the orbitofrontal cortex, located just above the eyes, the same area that functions abnormally in patients with obsessive-compulsive disorder and that is believed to underlie their compulsive behaviors.

“We always thought of drug addiction as a disease of the primitive parts of our brain, the limbic parts… the pleasure centers,” Volkow said in a 2002 lecture. “And here, the frontal cortex, which epitomizes the higher levels of our ‘reasoning’ human brain, appears to be involved.”

PET scans taken at Brookhaven National Laboratory suggest that the brains of obese individuals have fewer dopamine D2 receptors than do brains of normal controls. A radiolabeled compound (raclopride) that binds to the receptors was used to determine receptor concentration. Red spots in an averaged image of the control brains (top left) indicate a greater concentration of raclopride, and thus more D2 receptors, than are present in an averaged image of the obese group (top right). Overall brain metabolism, measured by the concentration of FDG, a radiotracer for glucose, did not differ significantly between the two groups (bottom panel). Since dopamine modulates motivation and reward circuits, the researchers concluded that dopamine deficiency in obese individuals may perpetuate pathological eating as a means to compensate for decreased activation of these circuits.

During the next few years, the Brookhaven scientists documented reduced levels of dopamine D2 receptors in the brains of alcoholics, heroin abusers and methamphetamine addicts. In addition, they found methamphetamine caused inflammatory changes in the brain that were associated with loss of memory, attention and motor skills.

In 2001, the Brookhaven group, led by Gene-Jack Wang, M.D., reported that obese people—like those addicted to alcohol, cocaine or methamphetamine—have lower-than-normal levels of dopamine D2 receptors.

“Individuals with low numbers of D2 receptors may be more vulnerable to addictive behaviors including compulsive food intake,” the researchers concluded. “We speculate that… decrements in D2 receptors perpetuate pathological eating as a means to compensate for the decreased activation of reward circuits, which are modulated by dopamine.”

Just because a person is vulnerable, however, doesn’t necessarily mean he or she will become addicted. Exercise, for example, has been shown to increase the level of D2 receptors and dopamine release in rats.

Volkow believes it may be possible to identify protective factors in humans, particularly in the age group most vulnerable to drug addiction—the adolescent.

“Very much the initiation of experimenting with drugs occurs in social settings, in group settings, in adolescents that want to actually be part of groups,” she says. “It’s a very important area of research to develop, so we can better understand the needs of kids and come with strategies to overcome situations where this response is going to be elicited.”

Volkow became a U.S. citizen in 1993. While her group published their findings prolifically, she rose through Brookhaven’s administrative ranks: director of the Nuclear Medicine Program (1994); chair of the Medical Department (1996); first director of the NIDA Regional Neuroimaging Center (1997); and the first woman to serve as Associate Laboratory Director for Life Sciences (1999).

“Nora is a dynamic, creative person with a broad vision of her field and a passion for science,” says former Brookhaven director John H. Marburger III, Ph.D., Science Advisor to the President and director of the Office of Science & Technology Policy.

“I asked her to be the Associate Director for Life Sciences at Brookhaven because I thought her dynamic style and clear vision for the work that could be done there would bring focus and energy to the division,” he says. “I think it prepared her well for her current position.”

Wolf died in 1998, but Volkow’s extraordinary partnership with Fowler and the other Brookhaven scientists continued to churn new scientific ground.

“It’s a very unusual relationship,” Fowler says. “We’re personally very close and also scientifically close, and we talk all the time… Every time I read something interesting and the same with her, we call and we talk about it.”

As Volkow’s perspective on addiction was broadening, so too were her opportunities. In the fall of 2002, Elias A. Zerhouni, M.D., director of the National Institutes of Health, asked her to lead NIDA, which funds the bulk of research conducted nationally (and internationally) on the health aspects of drug abuse and addiction.

Volkow, the scientist, wanted to continue her research. Volkow, the visionary, saw an opportunity to apply that research to improve the lives of people. Armed with Zerhouni’s promise that she could continue her research (she spends a long weekend every month at Brookhaven), in April 2003 she became the fifth person and first woman to direct the 30-year-old institute, which now has an annual budget of more than $1 billion.

Championing science

As a leader, Volkow is more revolutionary than bureaucrat. Her agenda is diverse and far-ranging, but its central theme is making connections—uniting physicians and pharmaceutical companies, drug courts and community groups to improve the treatment and prevention of addiction.

Among her top priorities: understanding the interactions between drug abuse, mental illness and AIDS.

Experimenting with drugs often begins during the novelty-seeking, peer pressured years of adolescence, and is a major contributor to the continued rise in HIV/AIDS in the United States. Drug use can lower resistance to risky behaviors like unprotected sex or sharing needles.

Drug abuse complicates treatment of other diseases, such as diabetes and cancer, yet addiction among patients with “co-morbid” conditions often is ignored, Volkow asserts. Limited access to drug treatment also contributes to the disproportional impact of AIDS and incarceration on minority groups.

African-Americans make up only 13 percent of the U.S. population, yet account for half of the nation’s HIV infections and more than 40 percent of jail and prison inmates. “These numbers,” she says, “are unacceptably high, embarrassingly high.”

Volkow’s blunt approach has been a “breath of fresh air” to retired Judge Karen Freeman-Wilson, former CEO of the National Association of Drug Court Professionals. According to association statistics, treatment of drug-addicted criminal offenders can reduce by at least half the rate of recidivism—the relapse to criminal behavior.

“She has been a tremendous help to us to really educate people on the science of addiction… but more importantly, the science of treatment,” explains Freeman-Wilson, a former Indiana attorney general who established that state’s first drug court in 1996.

During Volkow’s presentations, “I can see the light bulbs going on in the heads of judges who obviously operate on evidence,” she continues. “With that information, people have been able to say, ‘Well, maybe this isn’t just a bad person. Maybe this is a bad disease. And maybe we have to look at it and address it in a totally different way.’”

While many find Volkow’s frank speech refreshing, former Robert Wood Johnson Foundation President and CEO Steven A. Schroeder, M.D., wishes she and others in government would advocate more forcefully for treatment programs and policies—such as methadone and smoking cessation programs—that are already known to work.

“Unless I’m missing it… there is no federal champion for that. And that’s a shame. It’s a missed opportunity to make our country healthier,” says Schroeder, who directs the Smoking Cessation Leadership Center at the University of California at San Francisco.

Schroeder's point is well taken, Leshner responds, but Volkow's responsibility is much broader than advocacy. “She actually does advocate,” he says, “but ... her job is to make sure that the science is as good as it can be and then to bring the science to the attention of policy makers.”

Volkow believes that continued research is the way to overcome many of the challenges to improving treatment of addiction. PET studies, for example, are aiding the development of anti-obesity drugs that may interrupt the conditioned responses reinforcing compulsive drug-taking behavior as well as compulsive eating.

Brain imaging also could be used to measure the effectiveness of non-drug treatments. Since chronic drug abuse weakens the reward and motivation circuitry of the brain so that it only responds to more drug, it may be possible to “exercise” the brain in a way that increases the response to normal reinforcing stimuli and reduces the likelihood of relapse.

“Drugs permeate the medical system,” she says. “We’re doing a disfavor to the wellbeing of a wide variety of patients—whether they have lung disease, whether they have cancer, whether they have mental illness, whether they have an infectious disease—by not addressing the problem of addiction.”